LESSONS LEARNED: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy...

Mitochondrial dysfunction has been shown to be associated with normal ageing and may account for age-related vulnerability to disease. The increasing number of old people worldwide has created the need to find effective therapeutic agents to reduce the incidence of age-related disease. In the current report, we carried out an assessment of mitochondrial function in established young, middle-aged and old synaptosomal mitochondria bearing cybrids without or with melatonin treatment. The cybrids were generated by transferring isolated mitochondria from synaptosomes of brain cortical cells in mice to rho-zero mtDNA-less cells...

Over the course of history, human beings have never stopped seeking effective methods for information storage. From rocks to paper, and through the past several decades of using computer disks, USB sticks, and on to the thin silicon "chips" and "cloud" storage of today, it would seem that we have reached an era of efficiency for managing innumerable and ever-expanding data. Astonishingly, when tracing this technological path, one realizes that our ancient methods of informational storage far outlast paper (10,000 vs...

In our previous study, we uncovered a novel mechanism in which amelioration of Hutchinson-Gilford progeria syndrome (HGPS) phenotype is mediated by mitochondrial functional recovery upon rho-associated protein kinase (ROCK) inhibition. However, it remains elusive whether this mechanism is also applied to the amelioration of normal aging cells. In this study, we used Y-27632 and fasudil as effective ROCK inhibitors, and examined their role in senescence. We found that ROCK inhibition induced the functional recovery of the mitochondria as well as the metabolic reprogramming, which are two salient features that are altered in normal aging cells...

The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission...

Vascular smooth muscle (VSM) plays an important role in the regulation of vascular function. Identifying the mechanisms of VSM contraction has been a major research goal in order to determine the causes of vascular dysfunction and exaggerated vasoconstriction in vascular disease. Major discoveries over several decades have helped to better understand the mechanisms of VSM contraction. Ca 2+ has been established as a major regulator of VSM contraction, and its sources, cytosolic levels, homeostatic mechanisms and subcellular distribution have been defined...

Ursolic acid has various pharmacological activities, and can reduce blood fat as well as having antihepatic, antitumoral, anti-inflammatory and antiviral properties. However, the pro-apoptotic mechanism by which ursolic acid influences human prostate cancer requires additional study. The aim of the present study was to assess whether ursolic acid activates the apoptosis of prostate cancer and to investigate the mechanism by which the Rho-associated protein kinase 1 (ROCK1)/phosphatase and tensin homolog (PTEN) signaling pathway performs a role in ursolic acid-mediated cofilin-1 to induce apoptosis in human prostate cancer...

Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes...

Despite the development of newer anti-seizure medications over the past 50 years, 30-40% of patients with epilepsy remain refractory to treatment. One explanation for this lack of progress is that the current screening process is largely biased towards transmembrane channels and receptors, and ignores intracellular proteins and enzymes that might serve as efficacious molecular targets. Here, we report the development of a novel drug screening platform that harnesses the power of zebrafish genetics and combines it with in vivo bioenergetics screening assays to uncover therapeutic agents that improve mitochondrial health in diseased animals...

Epilepsy is a common disease of the central nervous system. This study aims to investigate the role of mitochondrial Rho (Miro) 1 in epilepsy using a mouse model of pilocarpine-induced status epilepticus (SE). Intraperitoneal injection of pilocarpine induced epileptic seizure in mice and significantly decreased Miro 1 expression in the hippocampus. Moreover, pilocarpine treatment increased the serum levels of heat shock protein 70 (HSP70) and S100 calcium binding protein B (S100B), and led to hippocampal neuronal injury and apoptosis...

Mitochondrial targeting and entry, two crucial steps in fighting severe diseases resulting from mitochondria dysfunction, pose important challenges in current nanomedicine. Cell-penetrating peptides or targeting groups, such as Rhodamine-B (Rho), are known to localize in mitochondria, but little is known on how to enhance their effectiveness through structural properties of polymeric carriers. To address this issue, we prepared 8 copolymers of 3-dimethyl(methacryloyloxyethyl)ammonium propane sulfonate and poly(ethyleneglycol) methacrylate, p(DMAPS-ran-PEGMA) (molecular weight, 18...

Dynamin-related peptide 1 (Drpl)-mediated mitochondrial fission is an important process associated with cardiac dysfunction under different pathological conditions. The aim of the present study was to investigate the expression of Drpl during inflammatory myocardial injury. Sprague‑Dawley rats were treated intraperitoneally with lipopolysaccharides (LPS). Furthermore, cultured H9C2 cardiomyocytes were treated with LPS, interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α). Total and mitochondrial proteins were isolated from the heart tissue of rats and from the H9C2 cardiomyocytes...

The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin, and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria...

In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho-GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double-knockout mouse embryos and single- and double-knockout embryonic fibroblasts, we demonstrate the essential and non-redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double-knockout cells...

Two types of spawning strategy have been described for ommastrephid squids: coastal and oceanic. It has been suggested that ancestral ommastrephids inhabited coastal waters and expanded their distribution into the open ocean during global changes in ocean circulation in the Oligocene. This hypothesis could explain the different reproductive strategies in oceanic squids, but has never been tested in a phylogenetic context. In the present study, we assess the coastal-to-open-ocean hypothesis through inferring the evolution of reproductive traits (spawning type) of ommastrephid squids using the phylogenetic comparative method to estimate ancestral states and divergence times...

Microtubule-dependent long-distance movement of peroxisomes occurs in mammalian cells. However, its molecular mechanisms remain undefined. In this study, we identified three distinct splicing variants of human mitochondrial Rho GTPase-1 (Miro1), each containing amino acid sequence insertions 1 (named Miro1-var2), 2 (Miro1-var3), and both 1 and 2 (Miro1-var4), respectively, at upstream of the transmembrane domain. Miro1-var4 and Miro1-var2 are localized to peroxisomes in a manner dependent on the insertion 1 that is recognized by the cytosolic receptor Pex19p...

Mitochondrial function is essential to meet metabolic demand of pancreatic beta cells respond to high nutrient stress. Mitophagy is an essential component to normal pancreatic β-cell function and has been associated with β-cell failure in Type 2 diabetes (T2D). Our previous studies have indicated that mitochondrial Rho (Miro) GTPase-mediated mitochondrial dysfunction under high nutrient stress leads to NOD-like receptor 3 (NLRP3)-dependent proinflammatory responses and subsequent insulin resistance. However, the in vivo mechanism by which Miro1 underlies mitophagy has not been identified...